The research proposed here is to investigate the mechanism of FeLV leukemogenesis. Studies of murine leukemia, murine mammary carcinoma, and avian leukosis suggest a clonal origin for these long-latency-type tumors induced by viruses lacking unique transforming genes. Three questions are of fundamental importance in understanding the mechanism of leukemia virus-induced leukemogenesis. 1) What is the nature of the preneoplastic cell? 2) What is the nature of the long latency period? 3) Where does the initial tumor cell originate? We intend to pursue these 3 major questions. Our approach of identifying preneoplastic cells by the expression of FOCMA-L, a non-viron tumor antigen, (by a radioimmune assay) will allow us to characterize the type(s) of cell involved, their differentiation stage and number of FOCMA-L molecules expressed per positive cell. These characteristics as well as those of shedding of FOCMA-L and FeLV antigens and susceptibility to immune injury, will be compared in preneoplastic lesions of regressor and progressor cats and with lymphomas to determine any differences which may be significant in leukemogenesis. We also plan to determine the actual target cells and specificities involved in the correlation of high antibody titers to viral proteins with FeLV resistance. To study the evolution of preleukemic to leukemic cells we have devised a technique involving transplantation in an outbred species. A new mixed leukocyte culture assay for cats, developed in our laboratory, will permit us to identify histocompatible animals. By using cats of different sexes in histocompatible pairs, and karyological analysis of tumor cells, it will be possible to determine whether tumor cells originated from preneoplastic donor bone marrow cells or whether a secondary event, such as release of FeLV (perhaps altered in a preneoplastic cell) and infection of thymocytes, is involved. This transplantation technique will also allow us to investigate the nature of the long latency period required for the evolution of FeLV preneoplastic lesions into tumors. This will be accomplished by dissecting time post-FeLV infection from thymic environment. An understanding of the mechanisms involved in the induction by feline leukemia virus of long latency leukemias and lymphomas is highly desirable for its own sake, as well as in the eventual application of this knowledge toward the prevention and therapy of human leukemias and lymphomas. In addition, elucidation of the mechanisms of leukemogenesis would increase our knowledge of carcinogenesis in general, as well as our basic understanding of cellular control mechanisms of gene expression.